Lipoprotein-Associated Phospholipase A2 (Lp-PLA2), also previously known in the art as Platelet Activating Factor Acetly Hydrolase (PAF acetyl hydrolase) is a member of the super family of phospholipase A2 enzymes that are involved in hydrolysis of lipoprotein lipids or phospholipids. It is secreted by several cells that play a major role in the systemic inflammatory response to injury, including lymphocytes, monocytes, macrophage, T Lymphocytes and mast cells.
During the conversion of LDL to its oxidised form, Lp-PLA2 is responsible for hydrolysing the sn-2 ester of oxidatively modified phosphatidylcholine to give lyso-phosphatidylcholine and an oxidatively modified fatty acid. Lp-PLA2 hydrolyzes the sn2 position of a truncated phospholipid associated with oxidized LDL. As a result, there is a generation of 2 inflammatory cell homing mediators (non-esterfied fatty acids (NEFA) and LYSO PC) Both NEFA and LYSO PCs are chematractants for circulating monocytes, play a role in the activation of macrophages and increase oxidative stress as well as affecting the functional and the immediate responses of T lymphocytes. Lp-PLA2 is bound in humans and pigs to the LDL molecule via lipoprotein B, and once in the arterial wall the oxidized LDL is susceptible to hydrolysis by Lp-PLA2.
Both of these products of Lp-PLA2 action are potent chemoattractants for circulating monocytes. As such, this enzyme is thought to be responsible for the accumulation of cells loaded with cholesterol ester in the arteries, causing the characteristic ‘fatty streak’ associated with the early stages of atherosclerosis, and inhibition of the Lp-PLA2 enzyme may be useful in preventing the build up of this fatty streak (by inhibition of the formation of lysophosphatidylcholine), and useful in the treatment of atherosclerosis.
In addition, it is proposed that Lp-PLA2 plays a direct role in LDL oxidation. This is due to the poly unsaturated fatty acid-derived lipid peroxide products of Lp-PLA2 action contributing to and enhancing the overall oxidative process. In keeping with this idea, Lp-PLA2 inhibitors inhibit LDL oxidation. Lp-PLA2 inhibitors may therefore have a general application in any disorder that involves lipid peroxidation in conjunction with the enzyme activity, for example in addition to conditions such as atherosclerosis and diabetes other conditions such as rheumatoid arthritis, myocardial infarction and reperfusion injury.
Lp-PLA2 is responsible for hydrolysing the sn-2 ester of oxidatively modified phosphatidylcholine to give lyso-phosphatidylcholine (lysoPC) and an oxidatively modified fatty acid. Both of these products of Lp-PLA2 action are potent chemoattractants for circulating monocytes. Therefore, Lp-PLA2 is thought to be responsible for the accumulation of cells loaded with cholesterol ester in the arteries, characteristic of atherosclerosis.
Osteopenia and osteoporosis are characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures. Osteoporosis affects 44 million Americans, or 55 percent of the people 50 years of age and older. One in two women and one in four men over age 50 will have an osteoporosis-related fracture in her/his remaining lifetime. Osteopenia and osteoporosis are responsible for more than 1.5 million fractures annually. The estimated national direct expenditures (hospitals and nursing homes) for osteoporotic hip fractures were $18 billion dollars in 2002, and the cost is rapidly rising.
One approach, for example, for treating bone disorders is inhibition of the osteoclast proton pump. See e.g., Blair et al., Science 1989, 245, 855-857; Finbow et al., Biochem. J. 1997, 324, 697-712; Forgac, M. Soc. Gen. Physiol. Ser. 1996, 51, 121-132; Baron et al., J. Cell. Biol. 1985, 101, 2210-2222; Farina et al., Exp. Opin. Ther. Patents 1999, 9, 157-168; and David, P. and Baron, R. “The Vacuolar II+TPase: A Potential Target for Drug Development in Bone Diseases” Exp. Opin. Invest. Drugs 1995, 4, 725-740.
Another approach to drug discovery for treating bone-related (and other) diseases involves the control of cellular signal transduction. See, for example, Missbach et al., “A Novel Inhibitor of the Tyrosine Kinase Src Suppresses Phosphorylation of Its Major Cellular Substrates and Reduces Bone Resorption in Vitro and in Rodent Models In Vivo.” Bone 1999, 24, 437-449; Connolly et al., Bioorg. & Med. Chem. Lett. 1997, 7, 2415-2420; Trump-Kallmeyer et al., J. Med. Chem. 1998, 41, 1752-1763; Klutchko et al., J. Med. Chem. 1998, 41, 3276-3292; Legraverend et al., Bioorg. & Med. Chem. 1999, 7, 1281-1293; Chang et al., Chem. & Biol. 1999, 6, 361-375; Lev et al. Nature 1995, 376, 737-784; Palmer et al., J. Med. Chem. 1997, 40, 1519-1529.
Some approaches for the treatment of bone disorders such as osteoporosis include, for example, estrogens, bisphosphonates, calcitonin, flavonoids, and selective estrogen receptor modulators. Other approaches include peptides from the parathyroid hormone family, strontium ranelate, and growth hormone and insulin-like growth response (see, for example, Reginster et al. “Promising New Agents in Osteoporosis,” Drugs R & D 1999, 3, 195-201).
The variety of different approaches represented by the therapeutic agents currently available or under study evidence the variety of biological factors influencing the competing processes of bone production and resorption. Although progress has been made towards developing therapeutic agents for osteoporosis and other bone disorders, to date, there is no cure for osteopenia and osteoporosis. Current medication for osteopenia and osteoporosis is aimed at reducing fracture risk and alleviating symptoms related to fracture.